Enhanced passive safety surveillance of high‐dose and standard‐dose quadrivalent inactivated split‐virion influenza vaccines in Germany and Finland during the influenza season 2021/22

Abstract Background Enhanced passive safety surveillance (EPSS) was conducted for quadrivalent inactivated split‐virion influenza vaccines (IIV4) in Germany (high dose [HD], aged ≥60 years) and in Finland (standard dose [SD], aged ≥6 months) at the beginning of the northern hemisphere 2021/22 influenza season. The primary objective was to assess adverse drug reactions (ADRs) occurring ≤7 days post‐vaccination. Methods Vaccinees were issued vaccination cards (VC) and were encouraged to report ADRs via an electronic data collection system or by telephone. ADRs were assessed by frequency, time to onset, intensity and by age group. The vaccinee reporting rate (RR) was calculated as the number of vaccinees reporting ≥1 ADR divided by total vaccinees. Reactogenicity was compared with previous experiences with each vaccine. Results Among 903 HD‐IIV4 vaccinees in Germany, 17 reported ≥1 ADR within ≤7 days post‐vaccination: RR, 1.88% (95% CI: 1.10, 3.00). Time to onset was known for 53/65 ADRs, all of which occurred ≤7 days post‐vaccination. In Germany, seven ADRs were reported that were not listed previously. Among the 1000 SD‐IIV4 vaccinees in Finland, 49 reported ≥1 ADR within ≤7 days post‐vaccination: RR, 4.90% (95% CI: 3.65, 6.43). Time to onset was known for 126/134 ADRs, of which 125 occurred ≤7 days post‐vaccination. In Finland, 21 ADRs were reported that were not listed previously. No ADRs reported during follow‐up were serious. Conclusions The EPSS for HD‐IIV4 and for SD‐IIV4 in the 2021/22 influenza season did not suggest any clinically relevant changes in safety beyond what is known/expected for IIV4s.


| INTRODUCTION
Influenza vaccines need to be updated each year to match the strains predicted by the World Health Organization to be circulating in the forthcoming influenza season. This presents specific challenges for the continued and timely monitoring of safety for new vaccines each season. Therefore, in 2014, the European Medicines Agency (EMA) introduced the requirement for manufacturers to conduct enhanced passive safety surveillance (EPSS). 1 The main aim of EPSS is to enhance safety signal detection in a routine clinical care setting by facilitating spontaneous reporting of adverse drug reactions (ADRs), in near real-time, following vaccine exposure in the relevant age groups. Thus, any potential clinically significant changes in the frequency and/or intensity of ADRs can be detected before the peak immunization period each year. 1 EPSS combines routine surveillance with clinical services to encourage patients and healthcare professionals (HCPs) to report adverse events. Unlike active surveillance, ADRs are not solicited with EPSS, and there is no active follow-up unless the individual reports an ADR and agrees to be contacted for further information. The ability of EPSS to improve ADR reporting rates (RRs) after vaccination has been shown in several studies. [2][3][4][5][6] Here we report the EPSS during the northern hemisphere (NH) 7 2021/22 influenza season for two quadrivalent inactivated split-virion influenza vaccines (IIV4s). In Germany, we assessed high-dose (HD)-IIV4 containing 60 μg per strain (Efluelda ® , Sanofi). 8 HD-IIV4 is licensed for use in adults aged ≥60 years and was launched in Germany in 2021. In people aged ≥65 years, HD-IIV3 vaccine versus standard dose (SD) IIV3 vaccine has been shown to reduce cases of influenza-like illness, as well as influenza-related hospitalization and pneumonia. 9 The addition of another B strain to HD-IIV3 vaccine to formulate the HD-IIV4 vaccine did not alter immunogenicity or safety. 10 In Finland, we assessed SD-IIV4 containing 15 μg per strain (Vaxigrip Tetra ® , Sanofi). 11 SD-IIV4 was first licensed in Europe in 2016 for use in individuals aged ≥3 years, and in 2017, this was expanded in some countries to include use in individuals aged ≥6 months. 11 Clinical studies have shown that SD-IIV4 vaccine is immunogenic in children, adults and older adults, and a large, randomized, placebo-controlled trial of children aged 6-35 months demonstrated efficacy of 71.7% (95% confidence interval [CI]: 43.7, 86.9) against laboratoryconfirmed severe influenza illnesses due to vaccine-similar strains. 11,12 The EPSS of HD-IIV4 and SD-IIV4 were conducted to detect relevant changes in the frequency or intensity of expected reactogenicity compared with previous experience with the IIV4s. In Germany and Finland, each EPSS included individuals who received one of the vaccines at the start of the NH 2021/22 influenza season, with safety data collected for up to 8 weeks post-vaccination using an electronic data capture (EDC) system with telephone reporting as back-up.

| Objectives
The primary objective for each vaccine was to estimate the vaccinee RR of suspected ADRs occurring ≤7 days post-vaccination in the overall population.
A secondary objective was to estimate the vaccinee RR occurring ≤7 days post-vaccination according to pre-defined age groups (≥6 months to <6 years, ≥6 to <13 years, ≥13 to <18 years, ≥18 to ≤65 years and >65 years) with SD-IIV4 vaccine in Finland. For both vaccines, a secondary objective was to estimate the vaccinee RR for serious suspected ADRs over the entire follow-up period.
A further secondary objective was to compare the vaccinee RR of suspected ADRs observed during the current EPSS with the established reactogenicity profile. In Germany, as this is was first season of EPSS for HD-IIV4 vaccine, ADRs listed in the Summary of Product Characteristics (SmPC) were used for reference. 8 For SD-IIV4 vaccine in Finland, rates were compared with the previous NH influenza season 13 and with the SmPC. 11

| Vaccines and vaccination
In Germany, participants received HD-IIV4 vaccine (

| Data collected
The medical dictionary for regulatory activities (MedDRA) was used to define ADRs by system organ class (SOC) and preferred term (PT).
Vaccinees were asked to report the intensity of ADRs as mild, moderate or severe. Serious ADRs were defined as those that resulted in death or are life-threatening, or that required inpatient hospitalization or the prolongation of existing hospitalization, or resulted in the persistence of significant disability or incapacity. ADRs that did not qualify as AEIs or in the RMP were termed as 'other ADRs'.

| Statistical analysis
The EPSS current interim guidance for seasonal influenza vaccines in the EU (EMA/PRAC/222346/2014) requires the system to be able to detect ADRs considered to be common, that is, expected to occur with a RR of ≥1%. 1 To meet this requirement, 1000 individuals vaccinated within 4 to 6 weeks were to be included across the participating sites in each country. This population size provides a > 99% probability of collecting ≥1 report of a common AE.
Overall, intensity was reported for 12 'other' ADRs, including one, four, and seven, that were mild, moderate and severe, respectively (Table 4). Among the seven severe 'other' ADRs, reported by two vaccinees, there was one event each of chills, fatigue, feeling hot, general physical health deterioration, influenza like illness, nasal congestion and oropharyngeal pain (Table 4). Most of the ADRs were of moderate or mild intensity ( who reported ≥1 suspected ADR, reported ≥1 AEI ( Table 2). The distribution of AEIs by age group is shown in Supporting information, Table S1.  T A B L E 4 Reporting of AEIs and 'other' ADRs in Germany (HD-IIV4) and Finland (SD-IIV4), by intensity (during the entire follow-up period)   CI: 0.07, 0.97) were substantially lower than those in the SmPC, which lists these events as very common (≥10%). 8 ADRs reported in Germany occurring ≤7 days post-vaccination, and which were not listed in the SmPC, were vaccination site warmth (one ADR), decreased appetite (two ADRs), influenzalike illness (one ADR), nasal congestion (one ADR) and general physical health deterioration (one ADR). ADRs reported in Germany occurring >7 days postvaccination that were not listed in the SmPC were heart rate increased (one ADR), cardiovascular disorder (one ADR) and hypertension (one ADR).

| SD-IIV4 in Finland
With SD-IIV4, the vaccinee RRs in the current 2021/22 influenza season were higher than in the 2020/21 influenza season (above upper limit of previous season's CI) for overall ADRs, ADRs occurring ≤7 days post-vaccination, and AEIs. 13  The main limitation of the study was that all ADRs were selfreported by vaccinees or their legal guardians and were not medically confirmed. To avoid bias in the collection of safety data, there was no possibility for follow-up with individuals at the site level.

| CONCLUSIONS
The NH 2021/22 EPSS results for HD-IIV4 vaccine in Germany and SD-IIV4 vaccine in Finland did not suggest any clinically significant change in safety beyond what is known or expected for IIV4s. Using EDC reporting with telephone back-up, the reactogenicity profiles of the vaccines were consistent with published rates of spontaneous ADR reports with other seasonal influenza vaccines, ranging from 20 to 90 reports per 1,000,000 people vaccinated. 7,[18][19][20][21] curation; formal analysis; writing-review and editing.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.13071.

DATA AVAILABILITY STATEMENT
The datasets generated and/or analysed during the current study, including the raw data, are not publicly available in order to safeguard the privacy of participants and the confidentiality and protection of their data, as well as protect commercially sensitive information. Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan and dataset specifications. Patient level data will be anonymized, and study documents will be redacted to protect the privacy of our trial participants. Further details on Sanofi's data sharing criteria, including required permissions to access the data, eligible studies and process for requesting access can be found at: https://www.vivli.org/.